Calcium-phosphorus-apatites have a peculiar performance as adsorbents for biopolymers, fluorine ions, heavy metal ions, etc. They have recently been regarded as useful as a chromatographic packing material for separation of proteins and enzymes with utilization of bioaffinities thereof. They have also attracted attention as substances capable of being used in bioceramic materials for artificial bones and teeth.
Processes for preparation of these apatites have been known for a long time. According to a rough classification, however, the following processes can be exemplified.
(1) Processes involving direct precipitation with ions in an aqueous solution, which are called wet synthesis processes.
A. Tiselius et al. developed a hydroxyapatite preparation technique according to the wet precipitation reaction process [Arch. Biochem. Biophys. 65, 132-155 (1956)]. Moreno et al. presented the conditions for synthesis of a hydroxyapatite with a Ca/P ratio of 1.67 [E. C. Moreno et al., J. Res. Natl. Bur. Stand. 72 A(6), 773-82 (1968)]. The results of an experiment following the above-mentioned conditions by Larsen et al. were reported [S. Larsen et al., Experientia 27 (4), 483-85 (1971)].
In these wet synthesis processes, it is difficult to consistently obtain a precipitate having a composition with the ratio of formulation, due to a very large number of factors, including the kinds and concentrations of raw material salts, the procedure and rate of mixing, and the pH adjustment in the step of mixing an aqueous solution of a calcium salt with an aqueous solution of a phosphorus compound to form the precipitate according to a direct ionic reaction for crystallization into an apatite. Therefore, a serious difficulty is encountered in controlling the atomic ratio Ca/P of calcium and phosphorus and the physicochemical properties of the formed powder with good repeatability. Moreover, many steps involving filtration, washing, drying, and pulverization of the precipitate are needed together with many apparatuses therefor, and the operations require much skill, thus presenting a number of difficulties.
(2) Processes involving a solid diffusion reaction, which are called dry synthesis processes.
These processes are suitable for synthesis of hydroxyapatite having a stoichiometrical composition, which is hard to prepare according to any process as mentioned in (1). Fowler synthesized hydroxyapatites of alkaline earth metal according to a solid reaction of a calcium, strontium, or barium salt of pyrophosphoric acid or carboxylic acid [B. O. Fowler, Inorg. Chem. 13 (1), 207-14 (1974)]. Since the reaction according to the dry synthesis process must be continued at high temperature for a long period of time, however, large energy is disadvantageously consumed. Further, a difficulty in obtaining a homogeneous composition ensues from the solid-solid reaction.
(3) Processes involving a high pressure reaction, which are called hydrothermal synthesis processes, and which are performed mainly for the purpose of obtaining large crystals.
Problems such as use of expensive apparatus and complicated operations are involved in these hydrothermal processes because the reaction is performed under high pressure.
Columns packed with hydroxyapatite have recently been marketed. This has enabled biopolymers of 10.sup.5 daltons or more to be separated and purified, which was previously impossible. Thus, they have been attracting attention as meeting industrialization of biotechnology requiring separation and purification of proteins, nucleic acids, enzymes, etc.
However, prior art packing materials consisting of hydroxyapatite are low in mechanical strength, liable to be divided into fine particles, poor in the repeatability of packing properties and chromatographic properties, and also, poor in durability or short in life span, leading to high cost, thus presenting various disadvantages. Therefore, they have not yet been widely employed, despite their excellent properties concerning separation and purification of biopolymers. Thus, removal of their disadvantages has been seriously demanded.
Specifically, since the conventional hydroxyapatite is prepared by the so-called wet synthesis process, control of the Ca/P ratio is difficult and removal of the phosphoric acids is insufficient, leading to disadvantages such as low resistance to strong alkalis as well as organic solvents.
Atkinson et al. synthesized a hydroxyapatite by a wet hydrolysis process and reported its aptitude for chromatography [A. Atkinson et al., J. Appl. Chem. Biotechnol. 23 (7), 517-529 (1973)]. However, the hydroxyapatite synthesized by the hydrolysis process is liable to form coarse particles due to aggregation of fine crystals under the influence of the particle form of a raw calcium phosphate material as well as idiomorphic crystals. These particles are defective in being liable to be finely divided because of the poor mechanical strength thereof during packing under high pressure and measurement work. As well, they are poor in flowability during packing since they are a powder consisting of aggregates of fine particles. Moreover, a serious difficulty is encountered in densely packing the packing material particles under the action of high pressure for providing uniformity of spaces between the packing material particles because of the above-mentioned poor mechanical strength of the particles. In addition, special attention must be paid to handling of the packed column for avoiding any change in the packing state in the column. Thus, many difficulties in the practical use of the packing material particles are involved.
A raw material powder of an apatite for preparation of a high density hydroxyapatite ceramic must be excellent in thermal stability since a molding thereof is to be sintered at high temperature. In this respect, an apatite having the same atomic ratio of calcium to phosphorus as the theoretical composition ratio is desirable. In this sense, an apatite prepared by the dry synthesis process capable of easily providing an apatite with the theoretical composition may be suitable as the raw material of ceramics. Since the apatite prepared by the dry synthesis process has already undergone the high temperature reaction for the apatite synthesis, the sintering activity of a powder thereof pulverized as the raw material of ceramics is low because of the thermal history of the apatite. Accordingly, sintering must be carried out at a higher temperature in order to obtain a dense sintered body. This is accompanied by such a disadvantage that the proportion of apatite decomposition increases with an increase in the temperature.
According to U.S. Pat. No. 4,097,935, a high density hydroxyapatite ceramic is obtained by forming a gelatinous precipitate of calcium phosphate in a solution having a pH of 10 to 12 by the precipitation process, and separating and sintering the same. As described above, however, the wet synthesis process is affected by a number of factors, so that a difficulty is experienced in controlling the process with good repeatability.
As a result of extensive investigations on the process for preparing a calcium-phosphorus-apatite in a simple manner with a few steps while obviating the defects of the prior art techniques as mentioned above, we have completed the present invention.
According to the present invention, there is provided a process for preparing a calcium-phosphorus-apatite in a manner quite different from those of the above-mentioned prior art techniques, and a calcium-phosphorus-apatite having novel properties which is obtained according to this process.